Overview
Name: NPT520-34
Therapy Type: Small Molecule (timeline)
Target Type: alpha-synuclein, Inflammation (timeline), Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis, Parkinson's Disease
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 1), Parkinson's Disease (Phase 1)
Company: Neuropore Therapies, Inc.
Background
This orally available, small-molecule antagonist of toll-like receptor 2 (TLR2) is in development for the treatment of Parkinson’s disease and ALS. TLR2 is a pattern-recognition, innate immune receptor expressed on neurons and glial cells. It recognizes aggregated proteins, downregulates autophagy, and its expression rises in Parkinson’s. The rationale for NPT520-34 is that it facilitates clearance of misfolded protein aggregation via boosting autophagy (Dzamko et al., 2017; Kwon et al., 2019; Kouli et al., 2019; Fiebich et al., 2018).
According to information on the company’s website, NPT520-34 attenuates neuroinflammation mediated by microglia and astrocytes, and reduces levels of neuropathic proteins including α-synuclein, superoxide dismutase-1, and Aβ. No preclinical data have been published for NPT520-34.
According to a presentation at the 2020 AAT-AD/PD Focus Meeting, NPT520-34 was originally discovered in a screen for compounds that enhance autophagic clearance of α-synuclein in cells. In the L61 α-synucleinopathy mouse model, treatment with this compound reportedly lowered the accumulation of toxic proteins and markers of inflammation, preserved dopamine signaling in the brain, and improved grip strength and walking. In the Line 41 β-amyloidosis model, the compound was reported to lower plaques and inflammation; in the SOD1-G93A amyotrophic lateral sclerosis mouse model, treatment reduced aggregates and inflammation in the spinal cord, and prolonged survival (Apr 2020 conference news).
Findings
Starting in May 2019, a single-site Phase 1 trial assessed the safety, tolerability, and pharmacokinetics of NPT520-34, given in capsule form to 49 healthy volunteers. Volunteers received single doses of 125, 250, 500, or 1000 mg, or multiple doses of 250 or 500 mg, or placebo, daily for 14 days. Results were presented at the 2020 AAT-AD/PD conference (Apr 2020 conference news). The drug displayed dose-linear pharmacokinetics, with a half-life of eight hours. The company reported no deaths, serious adverse events, or discontinuations due to drug effects. The most common adverse event was headache.
In August 2019, the U.S. FDA granted NPT520-34 orphan drug status for ALS (see press release).
For details on NPT520-34 trials, see clinicaltrials.gov.
Last Updated: 08 May 2020
Further Reading
No Available Further Reading
Overview
Name: LY3884961
Synonyms: PR001, PR001A
Therapy Type: DNA/RNA-based
Target Type: Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1/2)
Company: Eli Lilly & Co., Prevail Therapeutics
Background
PR001 is a gene-replacement therapy that uses adeno-associated virus 9 (AAV9) to deliver a functional copy of the GBA1 gene to the brain. GBA1 encodes the enzyme glucocerebrosidase (GCase), a lysosomal enzyme involved in the breakdown of glycosphingolipids. PR001 is being developed for Parkinson’s disease associated with GBA1 mutations, and for Gaucher disease. The therapy comprises a one-time injection into the cerebrospinal fluid in the cisterna magna at the base of the brain.
Up to 10 percent of people with Parkinson’s disease carry a mutation in one copy of GBA1 that reduces enzyme activity and affects lysosomal function. Homozygous GBA1 mutations cause Gaucher disease, a lysosomal storage disease, which can begin in infancy or childhood and affects multiple organ systems, sometimes including the nervous system.
PR001 has been tested in mouse models of GCase deficiency. In mice treated chronically with a GCase inhibitor, intraventricular injection of PR001 increased enzyme activity and reduced glycolipid accumulation for at least six months. In a genetic model of Gaucher disease, PR001 restored GCase activity and improved the mobility of the mice on a balance beam. PR001 lowered the accumulation of insoluble α-synuclein, the major component of Lewy bodies in PD and other synucleinopathies, in two different mouse models (Nov 2019 conference news, see also Abeliovich et al., 2021).
The gene therapy was tested in non-human primates, where injection of virus into the cisterna magna resulted in broad distribution of the virus in the brain and significant elevation of GCase protein in brain tissue. No toxicity was reported.
Findings
In July 2019, the FDA granted fast-track status to PR001 for PD.
In January 2020, Prevail Therapeutics began PROPEL, a Phase 1/2 sham-controlled trial in people with moderate to severe PD symptoms and a GBA mutation. Run at four academic medical centers and one clinical research organization in the U.S., the trial planned to enroll 16 participants, randomized to a one-time injection of high-dose virus, low-dose virus, or sham. The main study would last one year, with a four-year follow-up. The primary objective is safety and tolerability. Secondary and exploratory endpoints include blood and CSF measures of GCase, glycolipid metabolism, α-synuclein and neurofilament light chain, PR001 immunogenicity, measures of clinical and daily function, and MRI and dopamine imaging. One-year safety and biomarker data were expected in late 2020. The trial was planned to end in August 2026.
In August 2020, Prevail announced that serious adverse events had occurred three months after injection in the first treated PD-GBA patient, which the company attributed to an immune response to the AAV9 vector. The unspecified events reportedly resolved with immunosuppressive treatment. The study protocol was changed to an open-label design with no sham injection arm, and with concomitant administration of the immunosuppressants prednisone and sirolimus. Primary objectives were modified to include immunogenicity of AAV9 and GCase in blood and CSF, along with adverse events. In the patient, CSF GCase reportedly increased from undetectable to normal levels at three months. Subsequently, the company added rituximab to the immunosuppression protocol, and increased trial enrollment to 24. Recruitment was finished by July 2022, and the trial completion date is now June 2029.
In 2020, PR001 received orphan drug, rare pediatric drug, and fast-track designations for neuronopathic Gaucher disease, a form that affects the brain and spinal cord. Enrollment for an open-label Phase 1/2 trial in 15 infants and children with Gaucher disease started in June 2021; a dose-finding trial in adults began in December 2022. The studies are set to run until 2028 and 2030, respectively.
In January 2021, Prevail was acquired by Eli Lilly & Company (press release), and PR001 was renamed LY3884961.
In an April 30, 2024, investor’s call, Lilly said they had stopped the study in children with Gaucher disease. The trials in adults, and in people with PD, are continuing.
For details on LY3884961 trials, see clinicaltrials.gov.
Last Updated: 07 Feb 2023
Further Reading
No Available Further Reading
Overview
Name: LTI-291
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 2)
Company: Lysosomal Therapeutics Inc.
Background
LTI-291 is a small-molecule activator of glucocerebrosidase (GCase), a lysosomal enzyme involved in the breakdown of glycosphingolipids. Mutations in GBA1, the gene encoding GCase, are the leading genetic risk factor for the synucleinopathies Parkinson’s disease and dementia with Lewy bodies. GBA1 mutations that lower enzyme activity are associated with a higher risk of developing PD, more severe disease, and faster progressing disease.
No preclinical data have been published for this drug.
Findings
In 2017, Lysosomal Therapeutics completed two Phase 1 studies in the Netherlands. One trial examined safety and pharmacokinetics of single ascending doses in 40 healthy adults. A second trial analyzed 14 days of multiple dosing in 39 healthy older volunteers, age 50 to 75. According to results presented at the 2020 AAT-AD/PD Focus Meeting, LTI-291 was safe after single or multiple dosing. Its pharmacokinetics were dose-proportional, with a half-life in blood of 30 hours. The drug accumulated in the brain to about 1 percent of plasma levels, or enough to double GCase activity, based on its in vitro potency (Apr 2020 conference news).
At the same meeting, the company presented results of a Phase 1b study in PD patients with GBA1 mutations. Run from 2017 to 2018, it randomized 40 participants to 10, 30, or 60 mg LTI-291 or placebo daily for 28 days. The drug appeared safe. Treatment transiently increased the abundance of glycosphingolipid pathway intermediates measured in peripheral blood cells, which the authors equate to increased GCase activity.
A separate imaging study treated 14 GBA-PD patients with placebo, 10, or 60 mg LTI daily for 26 days, and analyzed changes in brain blood flow, FDG-PET glucose uptake, and fMRI functional connectivity. Treated patients consistently showed higher blood flow and glucose uptake; functional connectivity in their default mode networks returned toward normal. Group differences were not statistically significant in this small sample.
Last Updated: 30 Apr 2020
Further Reading
No Available Further Reading
Overview
Name: CDNF
Synonyms: cerebral dopamine neurotrophic factor
Therapy Type: Procedural Intervention, Other
Target Type: Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1/2)
Company: Herantis Pharma Plc, Renishaw plc.
Background
The neurotrophic peptide CDNF promotes survival of midbrain dopaminergic neurons, which degenerate in Parkinson’s disease. The peptide does not cross the blood-brain barrier. It is administered directly into the brain via a surgically implanted delivery device.
Unlike other neurotrophic factors, CDNF is not a secreted protein. It is found mainly in the lumen of the endoplasmic reticulum in cells. Studies suggest it regulates the unfolded protein response (UPR), a signaling pathway that contributes to ER stress and cell death in multiple neurodegenerative proteinopathies (reviewed in Huttunen and Saarma, 2019). CDNF knockout mice show age-dependent deficits in dopamine function in the brain and loss of enteric dopamine neurons, both of which occur in the early stages of PD (Lindahl et al., 2020).
Extensive preclinical work on CDNF has been done in the laboratory where it was discovered. In rodent models of toxin-induced dopaminergic cell loss, single intracerebral doses or chronic brain infusion of CDNF were reported to improve motor function and neuron survival and function (Lindholm et al., 2007; Voutilainen et al., 2011; Airavaara et al., 2012). CDNF also enhanced the therapeutic benefit of acute subthalamic deep-brain stimulation (DBS), a current treatment for PD, in a rat model of late-stage disease (Huotarinen et al., 2018).
The same group, as well as independent investigators, published data on a gene-therapy approach. Using viral vectors to express CDNF in the striatum protected neurons and improved motor behaviors in the 6-hydroxydopamine toxicity model of parkinsonism in rats (Bäck et al., 2013; Ren et al., 2013; Wang et al., 2017).
CDNF was reported to inhibit α-synuclein oligomer toxicity in cultured dopaminergic neurons (Latge et al., 2015). No data are published on CDNF in α-synuclein animal models.
In 6-OHDA-lesioned marmoset monkeys, CDNF treatment increased dopamine transporter (DAT) binding activity on PET scans, suggesting it protected dopaminergic neurons (Garea-Rodríguez et al., 2016).
In other disease models, CDNF improved memory in both APP/PS1 and wild-type mice after intrahippocampal injections of the peptide or gene therapy with a viral vector. Treatment caused no change in amyloid load or hippocampal neurogenesis in the AD mice (Kemppainen et al., 2015). CDNF reportedly promoted recovery in rat models of spinal cord injury and stroke (Zhao et al., 2016; Zhang et al., 2018).
Findings
In September 2017, Herantis and Renishaw began a Phase 1/2 study of CDNF and an experimental delivery device in people who have had idiopathic Parkinson’s disease for about a decade. Called TreatER, the trial enrolled 17 patients at three university hospitals in Finland and Sweden. Participants first underwent neurosurgical implantation of the infusion device in a procedure comparable to the placement of a DBS electrode in advanced PD. Then they received six monthly infusions of recombinant human CDNF, starting at 120 micrograms and escalating to 400 or 1,200 micrograms, or placebo, into their putamina. After six months, all groups were eligible to receive CNDF monthly for an additional six months, with four years of follow-up. Twenty-four endpoints cover safety and tolerability, plus multiple clinical measures of mood, cognition, motor function, non-motor symptoms and general function; device-related safety, accuracy of implantation and infusion success; formation of anti-CDNF antibodies; DAT PET imaging; and serum and CSF levels of CDNF and α-synuclein.
On February 25, 2020, Herantis announced partial results from the six-month placebo-controlled main study (press release; slide presentation). It reported no serious adverse events related to CDNF treatment, and only mild to moderate side effects that were similar in treated and placebo groups. Two patients left the study because of serious infections requiring hospitalization, probably related to the device implantation and infusion process. Both recovered, and surgical procedures were altered to prevent future infections, the company said.
In the DAT-PET study, one of the treatment groups reportedly had a 17 percent increase in DAT signal in the putamen after six months, compared with a decline in the other treatment group and placebo. All participants who completed the first stage decided to continue into the six-month extension, where they received CDNF monthly at the low or high dose.
In November 2020, the company announced it would stop developing CDNF by intracranial infusion, and instead pursue non-surgical modes of subcutaneous injection or intranasal delivery (press release). Both approaches are currently in preclinical stages (pipeline).
In March 2021 at AD/PD, 12-month TreatER trial results were presented. Compared to the first six months, fewer adverse events were reported in the extension phase, with no dose-limiting toxicities and no detection of anti-CDNF antibodies. Most drug-related side effects were mild to moderate, and all participants recovered. The most common were dyskinesias, headache, feeling cold, fever, or fatigue, impulse control disorder, nausea, and weight loss. On the exploratory efficacy endpoints, treatment did not worsen symptoms, and some patients showed signs of potential benefits. The low-dose group had a reduction in bradykinesia at six months, as measured with a movement-measuring device worn on the wrist. However, there was no significant difference between groups in the UPRDS motor score. DAT levels in the low-dose group remained stable after 12 months, while the other groups declined. A proteomics analysis of CSF found that changes in 50 previously selected CSF biomarkers were more prominent in the lower-dose group. In three patients, proteomics changes correlated with improvements in the UPRDS or DAT-PET.
For details on CDNF trials, see clinicaltrials.gov.
Last Updated: 21 Apr 2021
Further Reading
No Available Further Reading
Species: Rat
Genes: Psen1, App
Modification: Psen1: Knock-In; App: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Plaques
No plaques at 15 days of age.
Neuronal Loss
No neuron loss at 15 days of age.
Gliosis
No astrogliosis or microgliosis at 15 days of age.
Last Updated: 24 Apr 2020
Further Reading
No Available Further Reading
Overview
Name: Vafidemstat
Synonyms: ORY-2001
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Oryzon Corporate
Background
ORY-2001 is a dual inhibitor of the transcriptional co-regulator lysine-specific demethylase 1 (LSD1 or KDM1A) and the mitochondrial membrane protein monoamine oxidase B (MAO-B, see MedChemExpress). It is an oral, brain-permeable small molecule.
LSD1 catalyzes the removal of methyl groups from histones, contributing to the epigenetic modulation of gene expression. Alterations in epigenetic regulation of gene expression have been implicated in neuropsychiatric conditions and Alzheimer’s disease (Aug 2014 news; Nov 2014 news).
LSD1 is a regulator of hematopoiesis, and LSD1 inhibitors have been mainly investigated for leukemias and other cancers (reviewed in Fang et al., 2019). The enzyme is expressed in brain, and is the most abundant histone demethylase in the frontal cortex. In mice, it promotes neural-stem cell proliferation, nervous-system development, and survival of mature neurons (reviewed in Swahari and West, 2019).
MAO-B breaks down dopamine in the brain. Another MAO-B inhibitor, rasagiline, is approved to treat Parkinson’s disease, and has shown signs of efficacy in AD (Dec 2019 conference news).
In preclinical work, the inhibitor was reported to prevent development of cognitive impairment in a mouse model of Huntington’s disease, and in the SAMP8 mouse model of age-related cognitive decline (2016 AAIC abstract; Maes et al., 2020). In the SAMP8 mice, ORY-2001 reduced expression of inflammatory genes including S100A9, and modulated genes associated with neuroplasticity and behavior in SAMP8 mouse brain. Mice tolerated the compound without hematological side effects. ORY-2001 also reduced aggression and increased social behavior in SAMP8 mice. These effects were attributed to LSD1/KDM1A inhibition.
Findings
In May 2017, Oryzon presented results of Phase 1 safety testing of single- and multiple-ascending doses of ORY-2001 in 88 healthy young volunteers (May 2017 conference news). Single doses from 0.6 to 4 mg produced no serious adverse events or signals in clinical and laboratory safety measures. Five days of 2.5 mg/day caused a drop in platelet count, which rebounded after a week. A pharmacodynamic analysis revealed dose-dependent binding of the drug to LSD1 in peripheral blood mononuclear cells. In subsequent work, the drug was found to reach the brain. Safety of the 2.5 mg dose was reported in an elderly cohort (2019 AAIC abstract).
In June 2018, a Phase 2a safety trial started in mild to moderate Alzheimer’s disease. Called ETHERAL (Epigenetic Therapy in Alzheimer’s disease), it recruited 117 patients with CSF evidence of amyloid pathology at 17 sites in Spain, France, and the U.K. Participants received 0.6 or 1.2 mg or placebo daily for six months, followed by a six-month continuation when everyone received drug. The trial was not powered to detect clinical changes, but secondary endpoints included measures of cognition, agitation, apathy, depression, quality of life, and volumetric MRI. The trial evaluated eight CSF biomarkers of inflammation, synaptic integrity, and others.
In May 2019, the ETHERAL-U.S. trial began to enroll an intended 33 AD patients in four U.S. locations for an identical study.
In April 2020, the company presented preliminary data from the European six-month treatment (Apr 2020 conference news and slides). The drug met safety goals, with treated cohorts showing no more dropouts, adverse events, or changes to hematological parameters than the placebo group. The treated group had a reduction in the inflammatory biomarker YKL40 in CSF. There was a trend toward lower neurogranin levels with treatment in the group as a whole, and a post hoc analysis of mild or moderate subgroups found treatment-related changes in neurogranin or NfL in some subsets. Neither Aβ, total tau, phospho-tau, nor S100A9 changed with treatment. There was no effect on cognition. Pharmacodynamic assessments in peripheral blood cells indicated 60 to 80 percent occupancy of LSD1, but no MOAB inhibition.
At the same meeting, Oryzon reported that in an open-label study in 12 people with AD at a single site in Barcelona, Spain, a six-month course of 1.2 mg daily led to improvement on scales measuring agitation and aggression, as well as the total Neuropsychiatric Index and measures of caregiver burden (see 2020 AAT-ADPD poster). At meetings throughout 2019, the company had reported positive data on aggression from an open-label, similarly-sized trial in people with ADHD, borderline personality disorder, and autism spectrum disorder (Jul 2020 company press release).
A small, placebo-controlled study for multiple sclerosis is ongoing in Spain.
For details on Ory-2001trials, see clinicaltrials.gov and EU Clinical Trials Register.
Last Updated: 06 Aug 2020
Further Reading
No Available Further Reading
Overview
Name: Emrusolmin
Synonyms: Anle138b, TEV-56286
Chemical Name: 3-(1,3-Benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline), alpha-synuclein, Other (timeline)
Condition(s): Parkinson's Disease, Multiple System Atrophy
U.S. FDA Status: Parkinson's Disease (Phase 1/2), Multiple System Atrophy (Phase 2)
Company: MODAG GmbH, Teva
Background
Anle138b is an oral, brain-penetrant, general inhibitor of protein aggregation. It was identified in a high-throughput screen for small-molecule inhibitors of α-synuclein and prion protein oligomerization. The compound is being developed for treatment of the rapidly progressing synucleinopathy multiple-system atrophy (MSA) and for Parkinson's disease (PD). It could potentially be applied to other synucleinopathies, such as dementia with Lewy bodies (DLB).
This diphenyl pyrazole compound has been shown to suppress oligomer formation in vitro and in vivo. It inhibited pathogenic protein accumulation and neurodegeneration, and improved survival in mouse models of α-synuclein and prion disease (Apr 2011 conference news; Wagner et al., 2013; Vallabh et al., 2023).
Structural studies revealed that anle138b binding to α-synuclein fibrils involves stable polar interactions inside the tubular fibril cavity, and placed the small molecule's central pyrazole moiety near α-synuclein's protein backbone (Antonschmidt et al., 2022; Dervişoğlu et al., 2023).
In α-synuclein transgenic mouse models of PD, anle138b administration reduced protein deposition in brain and improved dopamine neuron function and movement, even when treatment began after symptoms developed (Wegrzynowicz et al., 2019; Mar 2015 conference news; Levin et al., 2014).
In a mouse model of MSA created by overexpressing human α-synuclein in oligodendrocytes, anle138b reduced α-synuclein oligomers, preserved dopaminergic neurons, and improved walking compared with nontreated controls (Heras-Garvin et al., 2019). In a model mimicking more severe MSA, anle138b slightly improved motor skills, but did not significantly change neurodegeneration or α-synuclein accumulation in glia in mice expressing α-synuclein and exposed to a mitochondrial toxin (Fellner et al., 2016).
Anle138b was also effective in mouse models of tau pathology, where treatment of young mice decreased neuron loss, increased survival, and improved cognition (Aug 2014 conference news; Wagner et al., 2015). Even in older tau mice with established pathology, the compound was able to lessen tau deposition and reverse metabolic decline (Brendel et al., 2019). It inhibited tau aggregation in cell culture models, as well (Dominguez-Meijide et al., 2020). Bioinformatics analyses proposed testable mechanisms of action for anle138b (Kondratyev et al., 2022; Hosseini-Gerami et al., 2023).
In the APP/PS1Δ9 mouse model of Aβ pathology, anle138b restored hippocampal synaptic plasticity and memory (Martinez Hernandez et al., 2018). A study comparing anle138b to the investigational α-synuclein immunotherapy Affitope PD03 reported that both improved PD-related outcomes such as α-syn oligomer levels, microglial activation, neurodegeneration in the substantia nigra, and gait (Lemos et al., 2020).
A PET tracer based on anle138b is in development (Kuebler et al., 2020; Orlovskaya et al., 2023).
Findings
In December 2019, MODAG began a Phase 1, first-in-human study of the safety, tolerability, and blood levels of orally administered anle138b in healthy adults. Held in Nottingham, U.K., the trial enrolled 68 volunteers, who received single ascending doses of 50 mg and higher, or multiple ascending doses for seven days, or matching placebo. Primary outcomes were adverse events, changes in clinical lab measures, electrocardiogram, vital signs, and physical exam. Secondary outcomes were blood concentrations of drug. An optional third study arm measured the effect of food on pharmacokinetics. The trial finished in August 2020. According to a company press release, doses up to 300 mg daily produced no side effects. The drug's half-life was 12 hours, and plasma levels significantly exceeded those required for efficacy in animal models. Uptake was not affected by food. Results were published after peer review (Levin et al., 2022).
In December 2020, the company began a Phase 1b study in 48 people with Parkinson’s disease, also in Nottingham. The trial assessed safety, tolerability, and pharmacokinetics of 150 mg and higher daily doses for seven days. Other endpoints included CSF drug levels and changes in motor function. The U.K. study was supported by the Michael J. Fox Foundation. It concluded in December 2022 after enrolling 70 participants. No results have been released.
In October 2021, MODAG and TEVA Pharmaceuticals announced their collaboration to develop anle138b for Parkinson’s disease and multiple systems atrophy (press release).
From September 2022 to February 2023, the companies conducted a drug-drug interaction study with the CYP1A2 and CYP3A4 probes, caffeine, midazolam, and fluvoxamine.
MODAG and TEVA plan to begin a Phase 2 efficacy study in late 2024, according to a presentation at the March AD/PD conference in Lisbon (Apr 2024 conference news). Called TOPAS-MSA, the study aims to enroll 160 people diagnosed clinically with possible or probable MSA, who are able to walk at least 30 feet unassisted, and are on stable medication. Participants will be randomized to 300 mg emrusolmin or placebo once daily for one year, against a primary endpoint of progression in a modified unified MSA rating scale (UMSARS) part I score. Secondary endpoints are safety and tolerability. A one-year, open-label extension is planned. The study will run in the U.S., France, Italy, Germany, Spain, Israel, and Japan. This trial does not appear in registries yet.
For details on anle138b trials, see clinicaltrials.gov.
Last Updated: 02 May 2024
Further Reading
No Available Further Reading
Overview
Name: MW151
Synonyms: MW01-2-151SRM, Minozac, MW01-2-151WH, compound 17
Chemical Name: 2-(4-(4-methyl-6-phenylpyridazin-3-yl)piperazin-1-yl) pyrimidine
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: ImmunoChem Therapeutics, LLC
Background
MW151 is an orally available, brain-penetrant, anti-inflammatory compound. Its target is undisclosed. MW151 was discovered by screening and optimizing compounds that inhibit proinflammatory cytokine production in activated glia cells in culture (Wing et al., 2006). MW151 does not block anti-inflammatory cytokines.
Neuroinflammation involving glial activation occurs in Alzheimer’s and other neurodegenerative diseases, and contributes to disease pathology and cognitive decline.
In preclinical work, MW151 suppressed microglia and astrocyte activation, and upregulation of the inflammatory cytokines IL1β, TNFα, and S100b after oligomeric human Aβ42 infusion into mouse brain. MW151 prevented loss of synaptic proteins and hippocampal-dependent behavioral deficits in the mice (Hu et al., 2007).
In an APP/PS1 transgenic mouse model, MW151 treatment early in life reduced subsequent neuroinflammation, preventing losses of synapses and synaptic plasticity. The drug did not affect amyloid plaque load (Bachstetter et al., 2012). MW151 also reduced acute inflammation after traumatic brain injury in the APP/PS1 mice, and improved cognitive outcomes, without lessening Aβ accumulation (Webster et al., 2015). In a mouse model of mixed vascular and amyloid pathology, the compound reduced inflammation and improved markers of hippocampal metabolism; the mice were reported to have shown a trend toward improved memory functions (Braun et al., 2022).
MW151 quelled inflammation, prevented seizures, and boosted cognition in models of traumatic brain injury (Lloyd et al., 2008; Bachstetter et al., 2015; Bachstetter et al., 2016; Chrzaszcz et al., 2010), and radiation- or seizure-induced cognitive impairment (Jenrow et al., 2013; Somera-Molina et al., 2009).
The drug lessened paralysis in a model of multiple sclerosis (Karpus et al., 2008) and enhanced efficacy of gene therapy in a mouse model for a neurodegenerative lysosomal storage disease (Macauley et al., 2014).
Findings
In October 2019, a Phase 1 first-in-human safety and pharmacokinetic study of MW151 began at Duke University, with support from the NIH SBIR/STTR funding program. The trial randomized 40 healthy adults to a single dose of 10, 20, 40, 80, or 160 mg, or placebo, in capsule form. The trial ended in September 2021, and results are posted on clinicaltrials.gov. The study reported no serious adverse events related to drug. The most common side effect was headache at the higher doses. Blood drug levels were dose-proportional.
MW189, an intravenous formulation of MW151, was tested in a Phase 1 trial in healthy adults, also at Duke (Van Eldik et al., 2021). THis formulation has now progressed to Phase 2 in people with hemorrhagic stroke. MW189 is intended for acute indications including traumatic brain injury (May 2017 conference news).
In July 2022, another Phase 1 began testing MW151 to treat cognitive impairment induced by whole-brain radiation in cancer patients.
For details on MW151 trials, see clinicaltrials.gov.
Last Updated: 08 Feb 2023
Further Reading
No Available Further Reading
Overview
Name: Inzomelid
Synonyms: Emlenoflast, IZD174, MCC-7840
Chemical Name: N-[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]-1-(propan-2-yl)-1H-pyrazole-3-sulfonamide
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued), Parkinson's Disease (Discontinued)
Company: Hoffmann-La Roche, Inflazome Ltd.
Background
Inzomelid is an oral, brain-penetrant inhibitor of inflammasomes containing NLRP3, or nod-like receptor family, pyrin domain-containing protein 3. Inflammasomes are multiprotein, cytosolic complexes that function as sensors in the innate immune system. Their activation by pathologic proteins and other stressors triggers production and secretion of proinflammatory cytokines IL1-β and IL-18, and can induce cell death. NLRP3-containing inflammasome activation occurs in many conditions where chronic inflammation plays a role, including Alzheimer’s and Parkinson’s diseases (reviewed in Heneka et al., 2018). Multiple NLRP3 inhibitors are in clinical trials for a range of inflammatory diseases (Li et al., 2023).
NLRP3 is a receptor for Aβ, and mediates the innate immune response to amyloid in microglia, cells involved Alzheimer’s pathogenesis (Halle et al., 2008). Deleting NLRP3 in the APP/PS1 mouse model diminishes Aβ deposition, synapse loss, and memory deficits (Heneka et al., 2013). Loss of NLRP3 also prevents tau tangle formation in human tau-expressing mice in response to injected Aβ (Ising et al., 2019).
No preclinical studies using inzomelid are published. However, a related NLRP3 inhibitor, MCC950, blocked inflammasome activation, promoted microglial clearance of Aβ, reduced Aβ accumulation, and improved cognitive function in APP/PS1 mice (Coll et al., 2015; Dempsey et al., 2017). MCC950 also prevented inflammasome activation by fibrillar α-synuclein, and led to less neuron loss and better dopaminergic signaling in Parkinson’s disease models (Gordon et al., 2018). The scientists behind these studies founded Inflazome, which holds patents on MCC950 and related compounds.
Findings
In March 2020, Inflazome announced completion of a Phase 1 trial of inzomelid in healthy adults and in patients with Cryopyrin-associated periodic syndrome. CAPS is an autoimmune disease caused by gain-of-function mutations in the NLRP3 gene, and affects both peripheral organs and the central nervous system. The trial enrolled 80 participants. Healthy adults received single or multiple ascending doses or placebo. CAPS patients received drug per an open-label protocol. Primary endpoints were safety, tolerability, and blood pharmacokinetics; Secondary outcomes were a pharmacodynamic marker of NLRP3 inhibition in blood, and reduction in CAPS symptoms in patients.
In a March 26, 2020, press release, Inflazome announced a linear relationship between dose and blood levels of drug and a correlation with NLRP3 activity. No data were provided. The release stated that the drug was safe and tolerable, and claimed that one CAPS patient showed rapid improvement after taking inzomelid, on unspecified clinical parameters. According to the company website, Inflazome was prioritizing development of inzomelid for CAPS, PD, AD, and amyotrophic lateral sclerosis.
In April 2020, the company registered a Phase 1 dose-escalation study in people with Parkinson’s disease. The study was to enroll six patients, starting in October 2020. The same month, Roche acquired Inflazome (C&EN News) and withdrew the Phase 1 Parkinson’s trial in December, before it began, citing business reasons.
Roche is currently developing the related NLRP3 inhibitor selnoflast.
Before the company’s acquisition, Inflazome was also developing an NLRP3-targeted PET tracer, with funding from the Michael J. Fox Foundation (press release). No further information has been made public on that effort.
For details on inzomelid trials, see clinicaltrials.gov
Last Updated: 21 May 2024
Further Reading
No Available Further Reading
Overview
Name: Edicotinib
Synonyms: JNJ-40346527, JNJ-527, PRV-6527
Chemical Name: 5-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(2,2,6,6-tetramethyloxan-4-yl)pyridin-3-yl]-1H-imidazole-2-carboxamide
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Janssen
Background
JNJ-40346527 is an oral, selective inhibitor of the colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase (for details, see on MedChemExpress). CSF-1R ligands promote survival, proliferation, and differentiation of macrophages and microglia; they also spur the growth of some cancers.
In Alzheimer’s disease, activation and proinflammatory cytokine release by microglia are essential mediators of pathology. This has spurred interest in drugs targeting microglial receptors.
JNJ-40346527 was tested in mouse models of prion disease and tauopathy (Mancuso et al., 2019). In the prion mice, the drug entered the brain and inhibited proliferation of microglia. In transgenic mice expressing human P30-1L tau, JNJ-40346527 blocked microglia proliferation and the production of the cytokines IL1β and TNFα. It reduced tau phosphorylation and neurodegeneration in the spinal cord, improved motor skills, and normalized the gene expression profile of microglia.
Findings
In November 2020, Janssen and the University of Oxford began a Phase 1 trial in people with mild cognitive impairment. The biomarker-based study will evaluate if JNJ-40346527 treatment changes CSF-1R signaling and microglia status. Three U.K. sites will enroll 54 participants with a Clinical Dementia Rating of 0.5 and randomize them 2:1 to receive 300 mg JNJ-40346527 twice daily or placebo for two weeks. Primary outcome is change in the concentration of CSF-1R ligands in cerebrospinal fluid. Secondary measures include unspecified biomarkers in CSF and plasma, CSF levels of microglia-derived extracellular vesicles and cells, CSF and plasma JNJ-40346527 levels, and safety assessments.
Depending on the results after two weeks of treatment, the trial will continue into a second randomized phase, at a dose to be determined. The trial will end in December 2021.
JNJ-40346527 was originally evaluated in cancer, arthritis, and inflammatory bowel disease, and has been tested extensively in people. It proved ineffective in Phase 2 trials for rheumatoid arthritis (Genovese et al., 2015) and Hodgkin’s lymphoma (von Tresckow et al., 2015).
In October 2019, JNJ-40346527 was reported to have been safe and well-tolerated but to have fallen short of primary endpoint in a trial for Crohn’s disease (press release, FierceBiotech story). Trials are ongoing in prostate cancer and acute myeloid leukemia.
For details on JNJ-40346527 trials, see clinicaltrials.gov.
Last Updated: 18 Dec 2020
Further Reading
No Available Further Reading
Comments
No Available Comments
Make a Comment
To make a comment you must login or register.